Estrogen receptor-α ablation reverses muscle fibrosis and inguinal hernias
Tanvi Potluri, … , Hong Zhao, Serdar E. Bulun
Tanvi Potluri, … , Hong Zhao, Serdar E. Bulun
Published February 4, 2025
Citation Information: J Clin Invest. 2025;135(6):e179137. https://doi.org/10.1172/JCI179137.
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Research Article Cell biology Muscle biology Reproductive biology

Estrogen receptor-α ablation reverses muscle fibrosis and inguinal hernias

Abstract

Fibrosis of the lower abdominal muscle (LAM) contributes to muscle weakening and inguinal hernia formation, an ailment that affects a noteworthy 50% of men by age 75 and necessitates surgical correction as the singular therapy. Despite its prevalence, the mechanisms driving LAM fibrosis and hernia development remain poorly understood. Using a humanized mouse model that replicates the elevated skeletal muscle tissue estrogen concentrations seen in aging men, we identified estrogen receptor-α (ESR1) as a key driver of LAM fibroblast proliferation, extracellular matrix deposition, and hernia formation. Fibroblast-specific ESR1 ablation effectively prevented muscle fibrosis and herniation, while pharmacological ESR1 inhibition with fulvestrant reversed hernias and restored normal muscle architecture. Multiomics analyses of in vitro LAM fibroblasts from humanized mice unveiled an estrogen/ESR1-mediated activation of a distinct profibrotic cistrome and gene expression signature, concordant with observations in inguinal hernia tissues in human males. Our findings hold significant promise for prospective medical interventions targeting fibrotic conditions and present non-surgical avenues for addressing inguinal hernias.

Authors

Tanvi Potluri, Tianming You, Ping Yin, John Coon V, Jonah J. Stulberg, Yang Dai, David J. Escobar, Richard L. Lieber, Hong Zhao, Serdar E. Bulun

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Figure 2

Fulvestrant treatment prevents and reverses well-established large hernias in mice.

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Fulvestrant treatment prevents and reverses well-established large herni...
(A) Schematic of hernia prevention study design (top) and measurement of scrotal hernias (bottom); fulvestrant was administered before hernia formation. Arrow indicates the week of pellet implantation (n = 10–15 per group, mean ± SEM, repeated-measures ANOVA). (B) Schematic of hernia treatment study design (top) and measurement of scrotal hernias (bottom); fulvestrant was administered after large hernias were formed. Arrow indicates the week of pellet implantation (n = 10–15 per group, mean ± SEM, repeated-measures ANOVA with Bonferroni multiple comparisons). In both A and B, the dotted line at 140 mm2 represents normal scrotum size before hernia development, and the orange shaded region represents large scrotal hernia size (>200 mm2). Created with BioRender (biorender.com). (C) Representative images of LAM morphology and Masson’s trichrome staining of LAMs from mice in the treatment study (B). Red arrows point to bilateral scrotal hernias in placebo-treated mice, while yellow arrows point to atrophied myofibers. (D and E) Quantification of the fibrotic area (D) and collagen content by hydroxyproline assay (E) in the mouse LAM treatment study (B and C) (n = 5–6 per group, median ± interquartile range, 2-way ANOVA with Bonferroni multiple comparisons; scale bars: 100 μm).